Apoptosome inactivation rescues proneural and neural cells from neurodegeneration

M. Cozzolino, E. Ferraro, A. Ferri, D. Rigamonti, F. Quondamatteo, H. Ding, Z. S. Xu, F. Ferrari, D. F. Angelini, G. Rotilio, E. Cattaneo, M. T. Carrí, Francesco Cecconi

Research output: Contribution to journalArticle

Abstract

Deficiency of the apoptosome component Apaf1 leads to accumulation of supernumerary brain cells in mouse embryos. We observed that neural precursor cells (NPCs) in Apaf1 -/- embryos escape programmed cell death, proliferate and retain their potential to differentiate. To evaluate the circumstances of Apaf1 -/- NPC survival and investigate their fate under neurodegenerative conditions, we established cell lines of embryonic origin (ETNA). We found that Apaf1 -/- NPCs resist common apoptotic stimuli and neurodegenerative inducers such as amyloid-β peptide (typical of Alzheimer's disease) and mutant G93A superoxide dismutase 1 (typical of familial amyotrophic lateral sclerosis). Similar results were obtained in Apaf1 -/- primary cells. When death is prevented by Apaf1 deficiency, cytochrome c is released from mitochondria and rapidly degraded by the proteasome, but mitochondria remain intact. Under these conditions, neither activation by cleavage of initiator caspases nor release of alternative apoptotic inducers from mitochondria takes place. In addition, NPCs can still differentiate, as revealed by neurite outgrowth and expression of differentiation markers. Our findings imply that the mitochondrion/apoptosome pathway is the main route of proneural and neural cells to death and that its inhibition prevents them from dismantling in neurodegenerative conditions. Indeed, the ETNA cell model is ideally suited for exploring the potential of novel cell therapies for the treatment of human neurodegenerations.

Original languageEnglish
Pages (from-to)1179-1191
Number of pages13
JournalCell Death and Differentiation
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2004

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Keywords

  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Apaf1
  • Apoptosis
  • Mitochondria

ASJC Scopus subject areas

  • Cell Biology

Cite this

Cozzolino, M., Ferraro, E., Ferri, A., Rigamonti, D., Quondamatteo, F., Ding, H., Xu, Z. S., Ferrari, F., Angelini, D. F., Rotilio, G., Cattaneo, E., Carrí, M. T., & Cecconi, F. (2004). Apoptosome inactivation rescues proneural and neural cells from neurodegeneration. Cell Death and Differentiation, 11(11), 1179-1191. https://doi.org/10.1038/sj.cdd.4401476